Is It Time to Deprioritize Preclinical Pain Research?

Is It Time to Deprioritize Preclinical Pain Research?

Editor’s Note:The first-ever North American Pain School (NAPS) took place June 26-30, 2016, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP); Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); and the Quebec Pain Research Network (QPRN), NAPS brought together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided first-hand reporting from the event, including summaries of scientific sessions and interviews with NAPS’ six visiting faculty members, along with coverage on social media. Below is a summary of a debate that took place at NAPS on the use of animals in preclinical research.

Dressed in their finest and still abuzz about an afternoon of white water rafting, early morning yoga, and a week of scientific lectures, workshops, and student presentations that stretched well into the evenings, the inaugural class of the North American Pain School (NAPS) took to the stage for one last scientific exercise: an educated, yet light-hearted debate perfect for a room full of clinician and basic science trainees.

Moderated by NAPS executive committee director Jeffrey Mogil, McGill University, Montreal, Canada, the debate saw the trainees address a provocative statement: “Preclinical (i.e., animal) pain research does not effectively lead to new pain treatments, and should be deprioritized accordingly.”

Serving as the backdrop for the debate was the ongoing, so-called failure of translation in the pain field: Only about 11 percent of all pain drugs entering Phase 1 clinical trials (after showing efficacy in animal studies) ever become approved by the US Food and Drug Administration (FDA). In the pain field, the failure to bring successful new drugs to market has been attributed to a number of factors, chief among them the relevance of animal research to the human experience of chronic pain.

Before the debate began, a show of hands revealed that the “pro” team (arguing to deprioritize preclinical research) had much to prove; the vast majority in the room showed immense support for the continued prioritization of animal research in the discovery process of bringing new treatments to patients.

The “pro” side

The debate opened with Emerson Krock, a PhD student at McGill University, who argued for the “pro” team. Krock came right out of the gate with a prime example of a failed drug class that had great promise due to exciting preclinical evidence for its efficacy, namely, substance P antagonists. “Total fail!” NAPS speaker Michael Gold, University of Pittsburgh, US, could be heard saying from the audience.

A neuropeptide released from pain neurons in the dorsal horn of the spinal cord, substance P plays a role in transmitting pain signals from the periphery into the central nervous system. Based on this, multiple drug companies developed receptor antagonists of this molecule. Yet the drugs failed to show analgesic efficacy in clinical trials, despite millions of dollars and decades of work invested into developing these compounds. “Despite a plethora of preclinical data, it didn’t work at all,” Krock said.

An additional barrier to translation, Krock said, is that it is difficult to know if an animal is experiencing pain when using reflexive behavioral tests that have become the mainstay of preclinical research. The workhorse for these tests is the von Frey hair (VFH), developed in 1896 by Maximilian von Frey. VFHs have been used to test mechanical sensitivity in humans, who can report on the level of pain they are experiencing from a VFH. When VFHs are applied to a rodent’s hind paw and the animal withdraws the paw at a given force, this is considered a “pain behavior,” but it is uncertain whether this kind of reflex response in animals, which of course cannot report their pain, is truly an indicator of an experience of pain.

As with the behavioral assays used in preclinical research, it’s unclear whether the animal models used in the lab have any relevance to human pain. “Putting a suture around a nerve to induce pain? This is obviously not a common experience in patients,” Krock said humorously. “Then there are the complete Freund's adjuvant and formalin models of [inflammatory] pain. I don’t know what those chemicals are really doing, but they certainly are not the reason patients are coming to see a doctor,” he added.

The short time course of most preclinical animal experiments is another problem. “We are interested in chronic pain,” Krock said. “If you do a study for a day or a week, that’s not chronic pain.”

Taking over for the “pro” side, Samantha Meints, a PhD student and rehabilitation psychology intern at VA Boston Healthcare System, US, further emphasized the difficulty of modeling human pain in animals. “We have talked a lot about the biopsychosocial model of pain in humans this week and how important it is in pain treatment, but we do not have a model of that nature in rodents,” she said. She argued that the multifaceted experience of pain in humans, which involves not just biological factors but also social and psychological factors, too, along with the diversity of patients with chronic pain, is not possible to replicate in rodents.

Another key issue is the underrepresentation of female animals in preclinical research. “Chronic pain is most commonly diagnosed in females, yet preclinical studies heavily rely on male animals,” she said.

The “con” side

As the debate continued, the “con” team (arguing to continue the prioritization of animal studies in pain research) noted the translational failures using this approach, but argued nonetheless in favor of animal research as an essential step in the discovery and development of new drugs and drug targets.

“If you want to know about the physiological mechanisms behind pain, then animal research is necessary,” said Katie Butera, a PhD student at the University of Florida, Gainesville, US. “In humans, you can’t dissect the spinal cord, remove the brain, or [sufficiently] control the environment,” she said.

Although there is a low success rate in bringing new drugs to the market following promising results in animals, Alexander Chamessian, an MD/PhD student at Duke University School of Medicine, Durham, North Carolina, US, emphasized that not all promising compounds in animals have failed in humans; in fact, there have been notable achievements. ”There are many examples of the successful translation of drugs from animals to humans,” said Chamessian. “The statement that animal research is useless [for translation] just isn’t categorically true.”

The “con” team further argued that preclinical animal research is an essential step not just for drug discovery but also for screening promising compounds for safety and efficacy in order to receive the go-ahead from the FDA to enter into human trials.

“Recent events in politics have shown us that ill-conceived decisions could have major repercussions,” said Butera as she revealed a slide with the newly created hashtag #animalRexit, a play on Brexit, the recent decision by the United Kingdom to leave the European Union. The audience burst into laughter as Mogil responded, “I actually mentioned a couple of nights ago that I was fully expecting Brexit and Donald Trump references tonight.”

Back-and-forth responses

After making their arguments, each side took time to respond to the assertions made by their opponents. On the “pro” side, Milind Muley, a PhD student at Dalhousie University, Halifax, Nova Scotia, Canada, said that another reason why preclinical animal research should be deprioritized is that it doesn’t address what is fundamental about pain in people. “Animal models do provide certain benefits, but the most important aspect of pain [in humans] is its spontaneous [ongoing] nature,” he said. “Most animal studies don’t focus on [measurements of] spontaneous pain,” relying instead on stimulus-evoked measurements.

Muley also stressed that the “pro” team only supported the assertion that pain investigators should deprioritize animal research rather than completely end it. “Once these problems in the animal models are fully addressed in the future, perhaps we can refocus on their use then. For now, however, there is just too much uncertainty with the data that are produced from them.”

The “con” team ended by acknowledging the concerns raised by Muley and his fellow debaters, but noted that these worries are increasingly recognized and are being addressed throughout the pain research field. Indeed, research labs across the globe are finding novel ways to test pain in animals that overcome previous shortfalls.

The verdict

As the debate closed, Mogil again surveyed the audience to determine the winning team. As the hands began to rise, the teams were noticeably anxious. Just as before the debate began, the majority of the room still supported the prioritization of preclinical animal pain research. But debates are not won on the basis of which side holds the majority, but rather on which side brings more people to its point of view. On that metric, it was clear: The “pro” team, arguing to deprioritize preclinical research, secured the most converts. Victory!

Nathan Fried is a postdoctoral fellow at the University of Pennsylvania.